In this cohort of 14
611 colon cancer patients treated on clinical trials of adjuvant chemotherapy, 1218 patients were black and 13
393 patients were white. We analyzed individual patient data from 12 clinical trials included in the ACCENT collaborative database. We found statistically significantly shorter overall survival for black patients compared with white patients with a 4.6% detriment in 5-year survival. Recurrence-free survival was also statistically significantly shorter for black patients compared with white patients with a 3.7% detriment in 3-year outcomes. Finally, we found no statistically significant difference in recurrence-free interval (time to recurrence) with a non-statistically significant detriment of 2.9% observed for 3-year outcomes.
The aim of adjuvant chemotherapy for colon cancer is to extend patient survival by delaying or preventing recurrence of colon cancer. Of the three endpoints considered in this analysis, recurrence-free interval (time to recurrence) is the most sensitive measure of the intended effect of chemotherapy. Unlike overall and recurrence-free survival, this endpoint would not be biased as a result of disparity in treatment for recurrent colon cancer, disparate care for comorbid conditions, or differential rates of death from causes unrelated to colon cancer. In this study, recurrence-free interval for black and white patients did not differ statistically significantly by race (HR of recurrence = 1.08, 3-year difference 2.9%, 4734 recurrences). The similar outcomes for recurrence-free interval suggest that equivalent treatment in the setting of a controlled clinical trial produces similar outcomes in both black and white patients with regard to tumor recurrence. Any differential response to adjuvant chemotherapy must be small.
The second endpoint considered in this study was recurrence-free survival (time to recurrence or death). In this analysis, black patients were found to have slightly worse recurrence-free survival compared with white patients (HR of recurrence or death = 1.14, 3-year difference 3.7%, 6231 events [recurrences or deaths]). Every patient who has an event (recurrence) for recurrence-free interval also has an event for recurrence-free survival; however, patients who die without recurrence are counted as an event for recurrence-free survival but not recurrence-free interval. These additional deaths (which were not preceded by recurrence, N = 6231–4734 = 1497) are likely unrelated to colon cancer and unlikely to be affected by adjuvant chemotherapy. Racial differences in comorbidity or general life expectancy are potential explanations for the statistically significant difference observed on this endpoint. Because life expectancy differs by race independent of a cancer diagnosis (22
), it is reasonable to conclude that some of the disparity in recurrence-free survival observed in this study is because of factors unrelated to adjuvant treatment for colon cancer.
Overall survival (time to death from any cause) was the final endpoint considered in this study. Despite similar stages of disease and equivalent adjuvant therapy, our analysis of the survival endpoint found a statistically significant difference by race with worse survival for black patients (HR of death = 1.22, 5-year difference 4.6%, 5539 deaths) when compared with white patients. The overall survival endpoint includes the same 1497 deaths not preceded by recurrence (27% of all deaths) included as events for recurrence-free survival, and overall survival is similarly susceptible to confounding by racial differences in comorbidity or general life expectancy. Additionally, the remaining 4042 deaths (73% of all deaths) were preceded by recurrence, and time to death for these patients may have been impacted by salvage treatment for recurrent disease. Because treatment for recurrent disease was outside the research protocols of the studies included in this analysis, racial differences in care for recurrent disease are also a potential confounder of overall survival.
There was no heterogeneity of the effect of race across studies for any of the endpoints considered. The effect of 5-FU treatment appears to be similar by race for the endpoints considered. The effect of race was also similar for our three endpoints by stage of disease, sex, and age.
Colorectal cancer remains a leading cause of cancer-related deaths in the United States. Across all stages of disease, survival for black patients continues to lag behind that reported for nonblack patients (1
). There have been a number of potential reasons proposed for this observation including later stage at diagnosis, differences in treatment, and the postulate that black patients have a biologically more aggressive disease or have a poorer response to currently used chemotherapy agents. Although these factors are important in patient outcome, perhaps the most relevant hypothesis is that African American patients are less likely to have access to routine cancer care, resulting in a poorer patient condition (eg, greater weight loss and poorer performance status) and later stage at diagnosis. In support of this postulate are data from the Black/White Cancer Survival Study Group (23
). Using the ACCENT clinical trial database, we have attempted to investigate this hypothesis. The ACCENT adjuvant colon cancer database offers several advantages over the use of other data sources. First, stage of disease is comparable within the constraints of the protocol entry criteria. Second, treatment and follow-up care are conducted according to a uniform standard.
This study has a few limitations. The ACCENT database does not include data on toxicity, comorbid conditions, and treatment for recurrent disease. The lack of these important data hinders our investigation of some important questions related to disparities in outcomes. Black vs white race is clearly not a randomized comparison, so we are forced to attempt to control for as many potentially prognostic covariates as possible to avoid a biased comparison by race.
The reason for the inferior overall survival for the black patients in this analysis warrants further consideration. In addition to the potential for noncancer deaths to contribute to differences in overall survival, the literature would support the notion that black patients may have a genetically unique response or toxicity to treatment compared with white patients. In the adjuvant trials included in this analysis, all patients receiving chemotherapy were treated with 5-FU either alone or in combination with other agents. 5-FU must first be activated by binding to methylenetetrahydrofolate reductase (MTHFR), a cellular molecule present at varying concentrations among patients(28
). It is known that the MTHFR
gene has several polymorphisms among populations, different MTHFR polymorphisms confer different levels of sensitivity to chemotherapy (28
), and that the polymorphisms are influenced by race. In a related finding, the pharmacogenetic syndrome, dihydropyrimidine dehydrogenase (DPD) deficiency, has been shown to predispose cancer patients to severe 5-FU toxicity (29
). As reported by Mattison et al. (30
), the prevalence of DPD deficiency was threefold higher in black healthy volunteers when compared with white volunteers; 8.0% and 2.8%, respectively. An analysis of 1402 patients receiving chemotherapy for metastatic colorectal cancer (3
) found that black patients had a different frequency of polymorphisms in key genes coding for enzymes involved in drug activation, metabolism, and disposition. The unavailability of toxicity data for the current analysis limits our ability to explore this question fully, but the similarities of recurrence-free interval outcomes by race suggest similar response to adjuvant chemotherapy.
The ability for patients to receive or to respond to salvage chemotherapy and/or surgery subsequent to recurrence could clearly impact on overall survival without affecting recurrence-free interval. The disparity in access to medical care between black and white patients is real (31
) but incompletely understood. Further study is warranted with the goal of improving overall survival in black patients with stage II and III colon cancer.
Black patients with resected stage II and III colon cancer treated with identical adjuvant therapy experienced poorer overall and recurrence-free survival but similar recurrence-free interval compared with white patients. The overall and recurrence-free survival endpoints include deaths not preceded by cancer recurrence and likely unrelated to colon cancer. This suggests that overall and recurrence-free survival differences may be largely because of factors unrelated to the patients’ adjuvant colon cancer treatment. Biological differences, differences in general health, and disparities in health care outside the clinical trial are possible explanations for these findings but will need to be pursued in other studies where data on patient care for recurrent cancer or comorbid conditions are available.